1-2478526-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_014638.4(PLCH2):c.175C>T(p.Arg59Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,460,542 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R59H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: PLCH2 NM_014638.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.05

Genes affected

PLCH2 (HGNC:29037): (phospholipase C eta 2) PLCH2 is a member of the PLC-eta family of the phosphoinositide-specific phospholipase C (PLC) superfamily of enzymes that cleave PtdIns(4,5) P2 to generate second messengers inositol 1,4,5-trisphosphate and diacylglycerol (Zhou et al., 2005 [PubMed 16107206]).[supplied by OMIM, Jun 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLCH2	NM_014638.4	c.175C>T	p.Arg59Cys	missense_variant	2/22	ENST00000378486.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLCH2	ENST00000378486.8	c.175C>T	p.Arg59Cys	missense_variant	2/22	1	NM_014638.4	P2
PLCH2	ENST00000419816.6	c.175C>T	p.Arg59Cys	missense_variant	2/22	5		P2
PLCH2	ENST00000449969.5	c.94C>T	p.Arg32Cys	missense_variant	2/22	5		A2
PLCH2	ENST00000609981.5	c.166C>T	p.Arg56Cys	missense_variant	3/4	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1460542 Hom.: 0 Cov.: 34 AF XY: 0.00000551 AC XY: 4 AN XY: 726570

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000810

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000826 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 22, 2023

The c.175C>T (p.R59C) alteration is located in exon 2 (coding exon 2) of the PLCH2 gene. This alteration results from a C to T substitution at nucleotide position 175, causing the arginine (R) at amino acid position 59 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Benign	0.0080	T
BayesDel_noAF	Uncertain	-0.040
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.49	T;.;T;T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.96	D;.;.;.
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.74	D;D;D;D
MetaSVM	Uncertain	0.0095	D
MutationTaster	Benign	1.0	D;D;D;N;N
PrimateAI	Pathogenic	0.83	D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	.;.;D;D
Vest4		0.64, 0.71, 0.68
MVP		0.85
MPC		0.96
ClinPred		0.95	D
GERP RS		4.7
Varity_R		0.41
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs372398573; hg19: chr1-2409965; COSMIC: COSV53939126; COSMIC: COSV53939126;